A Multicenter, Open-Label, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in First-line Treatment of Participants With Unresectable Hepatocellular Carcinoma
NCT ID: NCT01761266
Last Updated: 2022-04-05
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
954 participants
INTERVENTIONAL
2013-03-01
2021-03-10
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Lenvatinib
Participants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (\>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (\<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Lenvatinib
12 mg (or 8 mg) once daily (QD) oral dosing.
Sorafenib
Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
Sorafenib
400 mg twice daily (BID) oral dosing.
Interventions
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Lenvatinib
12 mg (or 8 mg) once daily (QD) oral dosing.
Sorafenib
400 mg twice daily (BID) oral dosing.
Other Intervention Names
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Eligibility Criteria
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Exclusion Criteria
* HCC with \>=50 percent liver occupation
* Clear invasion into the bile duct
* Portal vein invasion at the main portal branch (Vp4).
2. Participants who have received any systemic chemotherapy, including anti-vascular endothelial growth factor (VEGF) therapy, or any systemic investigational anticancer agents, including lenvatinib, for advanced/unresectable HCC. Note: Participants who have received local hepatic injection chemotherapy are eligible.
3. Participants who have received any anticancer therapy (including surgery, percutaneous ethanol injection, radio frequency ablation, transarterial \[chemo\] embolization, hepatic intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or any blood enhancing treatment (including blood transfusion, blood products, or agents that stimulate blood cell production, eg, granulocyte colony-stimulating factor \[G-CSF\]) within 28 days prior to randomization.
4. Participants who have not recovered from toxicities as a result of prior anticancer therapy, except alopecia and infertility. Recovery is defined as \< Grade 2 severity per Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0).
5. Significant cardiovascular impairment: history of congestive heart failure \> New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening.
6. Prolongation of corrected QT interval (QTc) interval to \>480 millisecond (ms)
7. Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib in the opinion of the investigator.
8. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low molecular weight heparin and factor X inhibitors which do not require INR monitoring is permitted. Antiplatelet agents are prohibited throughout the study.
9. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 28 days prior to randomization.
10. Gastric or esophageal varices that require interventional treatment within 28 days prior to randomization. Prophylaxis with pharmacologic therapy (eg, nonselective beta-blocker) is permitted.
11. Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 36 months.
12. Participants whose only target lesion(s) is in bone will be excluded.
13. Meningeal carcinomatosis.
14. Any history of or current brain or subdural metastases.
15. Participants having \>1+ proteinuria on urine dipstick testing will undergo a 24-hour urine collection for quantitative assessment of proteinuria. Participants with a urine protein \>=1g/24 hours will be ineligible.
16. Surgical arterial-portal venous shunt or arterial-venous shunt.
17. Any medical or other condition that in the opinion of the investigator would preclude the participant's participation in a clinical study.
18. Known intolerance to lenvatinib or sorafenib (or any of the excipients).
19. Human immunodeficiency virus (HIV) positive or active infection requiring treatment (except for hepatitis virus).
20. Any history of drug or alcohol dependency or abuse within the prior 6 months.
21. Any participant who cannot be evaluated by either triphasic liver computed tomography (CT) or triphasic liver Magnetic resonance imaging (MRI) because of allergy or other contraindication to both CT and MRI contrast agents.
22. Major surgery within 3 weeks prior to randomization or scheduled for surgery during the study.
23. Participants has had a liver transplant.
18 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
Eisai Limited
INDUSTRY
Responsible Party
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Locations
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Facility # 1
Los Angeles, California, United States
Facility # 1
Sacramento, California, United States
Facility # 1
San Francisco, California, United States
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Washington D.C., District of Columbia, United States
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Tampa, Florida, United States
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Duluth, Georgia, United States
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Lawrenceville, Georgia, United States
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Baltimore, Maryland, United States
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Detroit, Michigan, United States
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Kansas City, Missouri, United States
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St Louis, Missouri, United States
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East Orange, New Jersey, United States
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Brooklyn, New York, United States
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Lake Success, New York, United States
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New York, New York, United States
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Charlotte, North Carolina, United States
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Durham, North Carolina, United States
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Portland, Oregon, United States
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Austin, Texas, United States
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Lubbock, Texas, United States
Facility # 1
Seattle, Washington, United States
Facility # 1
Camperdown, New South Wales, Australia
Facility # 1
Wentworthville, New South Wales, Australia
Facility # 1
Woolloongabba, Queensland, Australia
Facility # 1
Fitzroy, Victoria, Australia
Facility # 1
Melbourne, Victoria, Australia
Facility # 2
Melbourne, Victoria, Australia
Facility # 1
Nedlands, Western Australia, Australia
Facility # 1
Brussels, , Belgium
Facility # 1
Edegem, , Belgium
Facility # 1
Liège, , Belgium
Facility # 1
Ottawa, Ontario, Canada
Facility # 1
Hefei, Anhui, China
Facility # 1
Beijing, Beijing Municipality, China
Facility # 2
Beijing, Beijing Municipality, China
Facility # 3
Beijing, Beijing Municipality, China
Facility # 1
Chongqing, Chongqing Municipality, China
Facility # 1
Fuzhou, Fujian, China
Facility # 2
Fuzhou, Fujian, China
Facility # 1
Guangzhou, Guangdong, China
Facility # 1
Harbin, Heilongjiang, China
Facility # 1
Changsha, Hunan, China
Facility # 1
Nanjing, Jiangsu, China
Facility # 1
Suzhou, Jiangsu, China
Facility # 1
Changchun, Jilin, China
Facility # 1
Dalian, Liaoning, China
Facility # 1
Jinan, Shandong, China
Facility # 1
Shanghai, Shanghai Municipality, China
Facility # 3
Shanghai, Shanghai Municipality, China
Facility # 1
Xi’an, Shanxi, China
Facility # 2
Xi’an, Shanxi, China
Facility # 1
Hangzhou, Zhejiang, China
Facility # 1
Tianjin, Zhejiang, China
Facility # 1
Nice, Alpes Maritimes, France
Facility # 1
Pessac, Gironde, France
Facility # 1
Toulouse, Haute Garonne, France
Facility # 1
Montpellier, Herault, France
Facility # 1
Rennes, Ille Et Vilaine, France
Facility # 1
Vandœuvre-lès-Nancy, Meurthe Et Moselle, France
Facility # 1
Amiens, Somme, France
Facility # 1
Créteil, Val De Marne, France
Facility # 1
Bordeaux, , France
Facility # 1
Lille, , France
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Lyon, , France
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Nord, , France
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Paris, , France
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Paris, , France
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Rhone, , France
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Heidelberg, Baden-Wurttemberg, Germany
Facility # 1
Tübingen, Baden-Wurttemberg, Germany
Facility # 1
Marburg, Hesse, Germany
Facility # 1
Hanover, Lower Saxony, Germany
Facility # 1
Cologne, North Rhine-Westphalia, Germany
Facility # 1
Essen, North Rhine-Westphalia, Germany
Facility # 1
Mainz, Rhineland-Palatinate, Germany
Facility # 1
Hong Kong, , Hong Kong
Facility # 2
Hong Kong, , Hong Kong
Facility # 3
Hong Kong, , Hong Kong
Facility # 1
Kowloon, , Hong Kong
Facility # 1
Petah Tikva, , Israel
Facility # 1
Torrette, Ancona, Italy
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Bari, , Italy
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Benevento, , Italy
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Bologna, , Italy
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Napoli, , Italy
Facility # 2
Napoli, , Italy
Facility # 1
Palermo, , Italy
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Roma, , Italy
Facility # 1
Nagoya, Aichi-ken, Japan
Facility # 1
Kashiwa, Chiba, Japan
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Matsuyama, Ehime, Japan
Facility # 1
Kurume, Fukuoka, Japan
Facility # 1
Sapporo, Hokkaido, Japan
Facility # 2
Sapporo, Hokkaido, Japan
Facility # 1
Nishinomiya, Hyōgo, Japan
Facility # 1
Kanazawa, Ishikawa-ken, Japan
Facility # 1
Kawasaki, Kanagawa, Japan
Facility # 1
Yokohama, Kanagawa, Japan
Facility # 1
Tsu, Mie-ken, Japan
Facility # 1
Ōmura, Nagasaki, Japan
Facility # 1
Ōsaka-sayama, Osaka, Japan
Facility # 1
Bunkyo-Ku, Tokyo, Japan
Facility # 1
Chuo-ku, Tokyo, Japan
Facility # 1
Koto-ku, Tokyo, Japan
Facility # 1
Minato-ku, Tokyo, Japan
Facility # 1
Musashino, Tokyo, Japan
Facility # 1
Shimonoseki, Yamaguchi, Japan
Facility # 1
Fukuoka, , Japan
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Hiroshima, , Japan
Facility # 1
Okayama, , Japan
Facility # 2
Osaka, , Japan
Facility # 1
Saga, , Japan
Facility # 2
Saga, , Japan
Facility # 1
Kuantan, Pahang, Malaysia
Facility # 1
George Town, Pulau Pinang, Malaysia
Facility # 1
Miri, Sarawak, Malaysia
Facility # 1
Batu Caves, Selangor, Malaysia
Facility # 1
Kuala Lumpur, , Malaysia
Facility # 1
Cebu City, , Philippines
Facility # 2
Cebu City, , Philippines
Facility # 1
Davao City, , Philippines
Facility # 1
Quezon City, , Philippines
Facility # 2
Quezon City, , Philippines
Facility # 1
Gdansk, , Poland
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Warsaw, , Poland
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Wroclaw, , Poland
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Arkhangelsk, , Russia
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Moscow, , Russia
Facility # 2
Moscow, , Russia
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Saint Petersburg, , Russia
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Saint Petersburg, , Russia
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Ufa, , Russia
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Singapore, , Singapore
Facility # 2
Singapore, , Singapore
Facility # 3
Singapore, , Singapore
Facility # 4
Singapore, , Singapore
Facility # 1
Goyang-si, Gyeonggi-do, South Korea
Facility # 1
Seongnam-si, Gyeonggi-do, South Korea
Facility # 2
Seongnam-si, Gyeonggi-do, South Korea
Facility # 1
Suwon, Gyeonggi-do, South Korea
Facility # 1
Daegu, Gyeongsangbuk-do, South Korea
Facility # 1
Hwasun, Jeollanam-do, South Korea
Facility # 1
Busan, , South Korea
Facility # 2
Busan, , South Korea
Facility # 3
Busan, , South Korea
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Incheon, , South Korea
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Seoul, , South Korea
Facility # 2
Seoul, , South Korea
Facility # 3
Seoul, , South Korea
Facility # 4
Seoul, , South Korea
Facility # 5
Seoul, , South Korea
Facility # 6
Seoul, , South Korea
Facility # 7
Seoul, , South Korea
Facility # 8
Seoul, , South Korea
Facility # 1
L'Hospitalet de Llobregat, Barcelona, Spain
Facility # 1
Santander, Cantabria, Spain
Facility # 1
Badajoz, , Spain
Facility # 1
Girona, , Spain
Facility # 1
Madrid, , Spain
Facility # 2
Madrid, , Spain
Facility # 3
Madrid, , Spain
Facility # 4
Madrid, , Spain
Facility # 1
Kaohsiung City, , Taiwan
Facility # 2
Kaohsiung City, , Taiwan
Facility # 1
Taichung, , Taiwan
Facility # 2
Taichung, , Taiwan
Facility # 1
Tainan City, , Taiwan
Facility # 2
Tainan City, , Taiwan
Facility # 1
Taipei, , Taiwan
Facility # 2
Taipei, , Taiwan
Facility # 3
Taipei, , Taiwan
Facility # 4
Taipei, , Taiwan
Facility # 5
Taipei, , Taiwan
Facility # 1
Taoyuan, , Taiwan
Facility # 1
Bangkoknoi, Bangkok, Thailand
Facility # 1
Pathum Wan, Bangkok, Thailand
Facility # 1
Ratchathewi, Bangkok, Thailand
Facility # 1
Muang, Changwat Chiang Rai, Thailand
Facility # 1
Muang, Chiang Mai, Thailand
Facility # 2
London, Greater London, United Kingdom
Facility # 1
London, Greater London, United Kingdom
Facility # 3
London, Greater London, United Kingdom
Facility # 1
Manchester, Greater Manchester, United Kingdom
Facility # 1
Liverpool, Merseyside, United Kingdom
Facility # 1
Glasgow, Strathclyde, United Kingdom
Facility # 1
Birmingham, West Midlands, United Kingdom
Countries
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References
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Piscaglia F, Ikeda K, Cheng AL, Kudo M, Ikeda M, Breder V, Ryoo BY, Mody K, Ren M, Ramji Z, Sung MW. Association between treatment-emergent hypertension and survival with lenvatinib treatment for patients with hepatocellular carcinoma in the REFLECT study. Cancer. 2024 Apr 15;130(8):1281-1291. doi: 10.1002/cncr.35185. Epub 2024 Jan 23.
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Cheng AL, Vogel A, Tovoli F, Ueshima K, Aikata H, Lopez CL, Pracht M, Meng Z, Daniele B, Park JW, Palmer D, Tamai T, Saito K, Dutcus CE, Lencioni R. Overall survival and objective response in advanced unresectable hepatocellular carcinoma: A subanalysis of the REFLECT study. J Hepatol. 2023 Jan;78(1):133-141. doi: 10.1016/j.jhep.2022.09.006. Epub 2022 Sep 20.
Huynh J, Cho MT, Kim EJ, Ren M, Ramji Z, Vogel A. Lenvatinib in patients with unresectable hepatocellular carcinoma who progressed to Child-Pugh B liver function. Ther Adv Med Oncol. 2022 Aug 24;14:17588359221116608. doi: 10.1177/17588359221116608. eCollection 2022.
Vogel A, Qin S, Kudo M, Su Y, Hudgens S, Yamashita T, Yoon JH, Fartoux L, Simon K, Lopez C, Sung M, Mody K, Ohtsuka T, Tamai T, Bennett L, Meier G, Breder V. Lenvatinib versus sorafenib for first-line treatment of unresectable hepatocellular carcinoma: patient-reported outcomes from a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Aug;6(8):649-658. doi: 10.1016/S2468-1253(21)00110-2. Epub 2021 Jun 2.
Okusaka T, Ikeda K, Kudo M, Finn R, Qin S, Han KH, Cheng AL, Piscaglia F, Kobayashi M, Sung M, Chen M, Wyrwicz L, Yoon JH, Ren Z, Mody K, Dutcus C, Tamai T, Ren M, Hayato S, Kumada H. Safety and efficacy of lenvatinib by starting dose based on body weight in patients with unresectable hepatocellular carcinoma in REFLECT. J Gastroenterol. 2021 Jun;56(6):570-580. doi: 10.1007/s00535-021-01785-0. Epub 2021 May 4.
Briggs A, Daniele B, Dick K, Evans TRJ, Galle PR, Hubner RA, Lopez C, Siebert U, Tremblay G. Covariate-adjusted analysis of the Phase 3 REFLECT study of lenvatinib versus sorafenib in the treatment of unresectable hepatocellular carcinoma. Br J Cancer. 2020 Jun;122(12):1754-1759. doi: 10.1038/s41416-020-0817-7. Epub 2020 Apr 8.
Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, Aikata H, Kawaguchi Y, Wada Y, Numata K, Inaba Y, Kuromatsu R, Kobayashi M, Okusaka T, Tamai T, Kitamura C, Saito K, Haruna K, Okita K, Kumada H. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020 Jan;55(1):113-122. doi: 10.1007/s00535-019-01642-1. Epub 2019 Nov 12.
Evans TRJ, Kudo M, Finn RS, Han KH, Cheng AL, Ikeda M, Kraljevic S, Ren M, Dutcus CE, Piscaglia F, Sung MW. Urine protein:creatinine ratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma. Br J Cancer. 2019 Jul;121(3):218-221. doi: 10.1038/s41416-019-0506-6. Epub 2019 Jun 28.
Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.
Other Identifiers
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2012-002992-33
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
E7080-G000-304
Identifier Type: -
Identifier Source: org_study_id
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